Project Summary The goal of this project is to understand the subcortical-hippocampal circuit mechanisms underlying social memory consolidation and brain state changes. The hippocampal mechanisms underlying spatial memory involve the reactivation of cells (active in the learning phase) during sharp-wave ripples (SWRs). However, it is not yet well known how these mechanisms extend to other types of declarative memory, such as social memory. Previously, I showed that the CA2 region can generate SWRs. In addition, CA2 has been reported to play a role in social behaviors. In the K99 of this award, I will study the underlying mechanisms of social memory. I will use large-scale electrophysiology and online optogenetic manipulations in different transgenic mouse lines. In addition to the hippocampus, the median raphe nuclei (MnR), which sends anatomical projections to CA2, has been also related to social behaviors. The MnR is one of the sources of serotonin production in the brain, which has been related to social and mood disorders both in rodents and humans. Furthermore, it was recently shown that MnR activity modulate hippocampal SWRs. During the R00 part of this award, I will investigate the role of the MnR-CA2 circuit in social memory. In order to address this, I will combine modern anatomical techniques, simultaneous electrophysiological recordings of MnR-hippocampus and simultaneous electrophysiological recordings and fiber photometry measurements to monitor the serotonergic tone from MnR. Finally, my previous work and others showed that CA2 activity correlates with hippocampal network transitions, such as SWRs states and running-immobility states. This suggests that CA2 might play a role in general brain state transitions. Interestingly, the MnR has also been reported to have a role in state transitions during waking and sleep. During the R00 phase, I will investigate the role of MnR-CA2 in gating global brain state transitions. I will use simultaneous electrophysiology from both regions combined with wide stimulation of MnR terminals in CA2. Furthermore, by using micro-LED embedded silicon based electrodes in specific transgenic animals, I will precisely dissect the contribution of the different MnR cells to each state transition. In summary, this proposal aims to understand the subcortical-hippocampal interactions underlying social memory and in general, brain state network dynamics. I will apply state of the art electrophysiological recordings, selective manipulation techniques and calcium signal recordings. The conclusions that I will be to extract from this project will shed light into our current basic understanding of neuropsychiatric diseases and mood disorders. The new technical skills that I will be able to acquire during the training period of this grant will be crucial in order to settle the basis of the research program of my independent laboratory studying subcortical- hippocampal interactions. In addition, the complementary skills that I will gain by training in writing, project managing and leadership, together with the guidance from my mentoring team and the diverse environments of Columbia University and NYU, will entitle me with the proper scientific skills to launch my independent career.